Publications by authors named "Fabien Rollot"

23 Publications

  • Page 1 of 1

Cumulative effects of therapies on disability in relapsing multiple sclerosis.

Mult Scler 2021 Jan 6:1352458520980366. Epub 2021 Jan 6.

Département de Neurologie, CHU Nantes, Nantes, France; CIC Inserm 1415, CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie, Inserm U1064, Nantes, France.

Background: Long-term effectiveness of treatment remains a key question in multiple sclerosis (MS) and the cumulative effects of past treatment have not been investigated so far.

Objective: Explore the relationship between treatment exposure and disability risk in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: A total of 2285 adult patients from the French nationwide cohort were included. Outcomes were irreversible EDSS4, and conversion to secondary progression of multiple sclerosis (SPMS). Associations between treatments and risk of disability were assessed using a novel weighted cumulative exposure model, assuming a 3-year lag to account for reverse causality. This flexible approach accounts for past exposure in a multivariate Cox proportional hazards model by computing a weight function.

Results: At baseline, mean ± standard deviation age of patients was 33.4 ± 8.9 years and 75.0% were women. A 15-year continuous treatment starting 20 years ago was associated with a decrease in risk of 26% for irreversible EDSS4, and 34% for SPMS compared to a 5-year treatment starting 10 years ago. The risk of disability decreased with increasing duration of exposure to disease-modifying treatment (DMT).

Conclusion: Long-term use of treatments in RRMS has a stronger beneficial cumulative impact than only early uses and delays the occurrence of moderate disability and conversion to SPMS.
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http://dx.doi.org/10.1177/1352458520980366DOI Listing
January 2021

Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Ann Neurol 2021 01 15;89(1):30-41. Epub 2020 Oct 15.

Department of Neurology, Multiple Sclerosis and Neuroinflammation, Pierre Wertheimer Neurological Hospital, Lyon Civil Hospices, Lyon, France.

Objective: The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG-Ab-associated disease (MOGAD).

Methods: This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time-to-event data and Kaplan-Meier curves for time to antibody negativity were performed for the objectives.

Results: Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow-up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12-1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280).

Interpretation: MOGAD patients differ in the clinical presentation at onset, showing an age-related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG-Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ANN NEUROL 2021;89:30-41.
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http://dx.doi.org/10.1002/ana.25909DOI Listing
January 2021

Predictive medicine in multiple sclerosis: A systematic review.

Mult Scler Relat Disord 2020 May 2;40:101928. Epub 2020 Jan 2.

SPHERE (methodS in Patient-centered outcomes & HEalth ResEarch) U1246, INSERM, Nantes University, Tours University, Nantes, France; Nantes University Hospital, Nantes, France. Electronic address:

Background: One of the main challenges in multiple sclerosis (MS) is to predict disease progression based on patient characteristics and therapeutic strategies. We therefore performed a systematic review to critically appraise the composite tools available for this purpose.

Methods: We performed electronic database searches in MEDLINE, EMBASE, Web of Science and the Cochrane Library. We included studies in English or French that developed and/or validated a predictive model for MS patients. Two reviewers independently screened articles by title and abstract. Three teams of two reviewers assessed the full text of each relevant study.

Results: Database searches yielded 6,035 studies after deduplication. Among the 42 screened full texts, 15 articles satisfied the eligibility criteria. Of these, six articles examined the development of predictive tools, six articles aimed to validate existing tools and three articles proposed both development and validation. We identified numerous methodological pitfalls, especially the lack of adequate validations in terms of discrimination and calibration. Only two scoring systems were externally validated several times: the Rio and the modified Rio scores. Nevertheless, their accuracies were highly variable, ranging from 65% to 91%.

Conclusions: Overall, there is a lack of validated predictive tools in MS, and further external validation of the existing ones are required. Demonstration of the clinical usefulness is also needed prior to being transferred into clinical practice. Finally, our study illustrates that the MS literature needs to integrate good standards in developing and validating predictive models.
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http://dx.doi.org/10.1016/j.msard.2020.101928DOI Listing
May 2020

Frequency of myelin oligodendrocyte glycoprotein antibody in multiple sclerosis: A multicenter cross-sectional study.

Neurol Neuroimmunol Neuroinflamm 2020 03 13;7(2). Epub 2019 Dec 13.

From the Service de Neurologie (Á.C.-C., F.D.-D., S.V., R.M.), Sclérose en Plaques, Pathologies de La Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; Centre de Référence pour Les Maladies Inflammatoires Rares Du Cerveau et de La Moelle (MIRCEM) (Á.C.-C., F.D.-D., S.V., R.M.), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Lyon, France; Centre de Recherche en Neurosciences de Lyon (Á.C.-C., H.I., A.R., R.M.), U1028 INSERM, UMR5292 CNRS, Lyon, France; Département de Neurologie (N.C., L.K., J.D.S.), Centre Hospitalier Universitaire de Strasbourg, France; Biopathologie de La Myéline (N.C., J.D.S.), Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, France; Centre D'investigation Clinique (N.C., J.D.S.), INSERM U1434, Centre Hospitalier Universitaire de Strasbourg, France; Centre de Recherche en Neurosciences de Lyon (F.R., R.C., S.V.), Observatoire Français de La Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, Lyon, France; and Université Claude Bernard Lyon 1 (F.R., R.C., S.V.), F-69000 Lyon, France; Hospices Civils de Lyon, Lyon, France.

Objective: To address the frequency of myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) in an unselected large cohort of adults with MS.

Methods: This is a cross-sectional study in 2 MS expert centers (Lyon and Strasbourg University Hospitals, France) between December 1, 2017, and June 31, 2018. Patients aged ≥18 years with a definite diagnosis of MS according to 2010 McDonald criteria were tested for MOG-Ab by using a cell-based assay (CBA) in Lyon and subsequently included. Positive samples were tested by investigators blinded to the first result with a second assay in a different laboratory (Barcelona, Spain) by using the same plasmid and secondary Ab.

Results: Serum samples from 685 consecutive patients with MS were analyzed for MOG-Ab. Median disease duration at sampling was 11.5 (interquartile range, 5.8-17.7) years, and 72% were women. Two (0.3%) patients resulted to be MOG-Ab-positive. The 2 patients were women aged 42 and 38 at disease onset and were diagnosed with secondary and primary progressive forms of MS, respectively. This positive result was confirmed by the CBA in Barcelona.

Conclusion: Our findings indicate that MOG-Ab are exceptional in MS phenotype, suggesting that the MOG-Ab testing should not be performed in typical MS presentation.
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http://dx.doi.org/10.1212/NXI.0000000000000649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943364PMC
March 2020

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.

JAMA Neurol 2020 01;77(1):94-102

CHU de Nantes, Service de Neurologie, CIC015 INSERM, Nantes, France.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated.

Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013.

Design, Setting, And Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018.

Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation.

Main Outcomes And Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016).

Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016.

Conclusions And Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.
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http://dx.doi.org/10.1001/jamaneurol.2019.2670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724170PMC
January 2020

Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis.

Neurology 2019 08 12;93(7):e635-e646. Epub 2019 Jul 12.

From INSERM (D.-A.L., L.B.), CIC 0004, Nantes; CRTI-INSERM UMR U1064 (D.-A.L.), Université de Nantes; Service de Neurologie (D.-A.L., S.W., L. Michel), CHU Nantes; Centre des Neurosciences de Lyon (R.C., F.R., S.V.), Observatoire Français de la Sclérose en Plaques, INSERM 1028 and CNRS UMR5292, Lyon; Université Claude Bernard Lyon 1 (R.C., F.R., S.V.), Université de Lyon; Department of Neurology (M.D.), Nancy University Hospital; Université de Lorraine (M.D.), EA 4360 APEMAC, Vandoeuvre-Lès-Nancy; Department of Neurology and Clinical Investigation Center (J.D.S.), CHU de Strasbourg, INSERM 1434; Department of Neurology (D.B.), CHU de Toulouse; Service de Neurologie (B. Brochet), CHU de Bordeaux; Service de Neurologie (J.P.), Hôpital de la Timone, CRMBM, CNRS, APHM, Aix Marseille Univ, Marseille; Univ Lille (P.V.), CHU Lille, LIRIC (Lille Inflammation Research International Center), INSERM UMR995; Service de Neurologie (G.E., L. Michel), CHU de Rennes; CRCSEP Nice (C.L.-F.), Neurologie Pasteur 2, Université Nice Cote d'Azur, Nice; Service de Neurologie (P. Clavelou), CHU de Clermont-Ferrand; Service de Neurologie (E.T.), CHU de Nîmes; Department of Neurology (J.-P.C.), Hôpital Nord, CHU Saint-Étienne; Service de Neurologie et Faculté de Médecine de Reims (A.T.), CHU de Reims, URCA; Service de Neurologie (B.S.), CHU Saint-Antoine; Service de Neurologie (A.A.K.), CHU d'Amiens; Service de Neurologie (P. Cabre), CHU de Fort de France; Service de Neurologie (C. Lubetzki, C.P.), CHU Pitié-Salpêtrière; Service de Neurologie (E.B.), CHU de Besançon; Service de Neurologie (O.H.), CH de Poissy; Service de Neurologie (T.D.), CH de Saint-Denis; Service de Neurologie (T.M.), CHU de Dijon; Service de Neurologie (O.G.), Fondation Rothschild; Service de Neurologie (B. Bourre), CHU de Rouen; Department of Neurology (A.W.), Hôpital Henri Mondor, Créteil; Service de Neurologie (P.L.), CHU de Montpellier; Service de Neurologie (L. Magy), CHU de Limoges; Service de Neurologie (G.D.), CHU de Caen; CRC SEP and Department of Neurology (A.-M.G.), CHU Bretonneau, Tours; Department of Neurology (N.M.), CHU La Milétrie, Poitiers; Department of Neurology (C. Labeyrie), CHU Bicêtre, Le Kremlin Bicêtre; Department of Neurology (I.P.), Hôpital Sud Francilien, Corbeil Essonnes; Department of Neurology (C.N.), CHU Versailles; Department of Neurology (O.C.), CHU de Grenoble; Ecole des Hautes Etudes en Santé Publique (E.L.), Rennes; Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation (S.V.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron; and INSERM (Y.F.), UMR 1246-SPHERE, Nantes University, Tours University, Nantes, France.

Objective: In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques.

Methods: A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.

Results: The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, < 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, < 0.001).

Conclusions: After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.

Classification Of Evidence: This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.
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http://dx.doi.org/10.1212/WNL.0000000000007938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715507PMC
August 2019

Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease.

J Neuroinflammation 2019 Jul 2;16(1):134. Epub 2019 Jul 2.

Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Lyon, France.

Background: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are related to several acquired demyelinating syndromes in adults, but the therapeutic approach is currently unclear. We aimed to describe the response to different therapeutic strategies in adult patients with relapsing MOG-Ab-associated disease.

Methods: This is a retrospective study conducted in France and Spain including 125 relapsing MOG-Ab patients aged ≥ 18 years. First, we performed a survival analysis to investigate the relapse risk between treated and non-treated patients, performing a propensity score method based on the inverse probability of treatment weighting. Second, we assessed the annualised relapse rates (ARR), Expanded Disability Status Scale (EDSS) and visual acuity pre-treatment and on/end-treatment.

Results: Median age at onset was 34.1 years (range 18.0-67.1), the female to male ratio was 1.2:1, and 96% were Caucasian. At 5 years, 84% (95% confidence interval [CI], 77.1-89.8) patients relapsed. At the last follow-up, 66 (52.8%) received maintenance therapy. Patients initiating immunosuppressants (azathioprine, mycophenolate mophetil [MMF], rituximab) were at lower risk of new relapse in comparison to non-treated patients (HR, 0.41; 95CI%, 0.20-0.82; p = 0.011). Mean ARR (standard deviation) was reduced from 1.05(1.20) to 0.43(0.79) with azathioprine (n = 11; p = 0.041), from 1.20(1.11) to 0.23(0.60) with MMF (n = 11; p = 0.033), and from 1.08(0.98) to 0.43(0.89) with rituximab (n = 26; p = 0.012). Other immunosuppressants (methotrexate/mitoxantrone/cyclophosphamide; n = 5), or multiple sclerosis disease-modifying drugs (MS-DMD; n = 9), were not associated with significantly reduced ARR. Higher rates of freedom of EDSS progression were observed with azathioprine, MMF or rituximab.

Conclusion: In adults with relapsing MOG-Ab-associated disease, immunosuppressant therapy (azathioprine, MMF and rituximab) is associated with reduced risk of relapse and better disability outcomes. Such an effect was not found in the few patients treated with MS-DMD.
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http://dx.doi.org/10.1186/s12974-019-1525-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607517PMC
July 2019

Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: A retrospective multicentric study.

Mult Scler 2020 07 31;26(8):936-944. Epub 2019 May 31.

Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Bron, France; Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle and INSERM U1028, CNRS UMR 5292, Lyon 1 University, Center for Research in Neuroscience of Lyon, Lyon, France.

Objectives: We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis.

Material And Methods: We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0.

Results: Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively),  = 0.007 and  = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group,  = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%),  < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0-4.0)) compared to SM patients (2.0, (1.0-3.0)),  = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01-1.95,  = 0.046).

Conclusion: SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.
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http://dx.doi.org/10.1177/1352458519849511DOI Listing
July 2020

Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS.

Mult Scler 2019 04 20;25(4):591-600. Epub 2018 Mar 20.

Service de Neurologie A, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France/Observatoire Français de la Sclérose en Plaques (OFSEP), Lyon, France/Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR5292, Equipe Neuro-Oncologie et Neuro-Inflammation, Lyon, France/Université de Lyon 1, Lyon, France.

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses.

Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy.

Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992-1995 and 2005-2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis.

Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78).

Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.
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http://dx.doi.org/10.1177/1352458518763080DOI Listing
April 2019

Aquaporin 4 distribution in the brain and its relevance for the radiological appearance of neuromyelitis optica spectrum disease.

J Neuroradiol 2019 Apr 11. Epub 2019 Apr 11.

Université Lyon 1, Laboratoire d'Anatomie de Rockefeller,Centre Hospitalier Lyon Sud, Service de Radiologie, Pierre Bénite, CREATIS-LRMN, CNRS/UMR/5220-INSERM U630, Villeurbanne, France.

Background And Purpose: To determine the precise incidence of lesions at sites of high Aquaporin-4 expression (hAQP4) and their possible association with known neuromyelitis optica spectrum disease (NMOSD) lesions patterns.

Materials And Methods: A retrospective analysis of brain and, when available, spinal cord MRI scans of 54 NMOSD patients recruited among the French NMOSD cohort was performed. Brain lesions were annotated as MS-like, non-specific, or evocative of NMOSD. The topography of hAQP4 was reassessed by human brain atlas. The incidence of lesions in hAQP4 and their association with lesions evocative of NMOSD was estimated.

Results: Among those included (41/54 female, mean age:45 years) 47/54(87%) presented brain lesions. Twenty-six/47(55%) had lesions in hAQP4. Thirty-two/54 patients(60%) had lesions considered evocative of NMOSD. The majority of them also presented lesions in hAQP4 (65%, 21/32). Patients with lesions in hAQP4 and lesions evocative of NMOSD demonstrated more extensive myelitis compared to the other patients (7[6-10] versus 4[3-5] vertebral segments, P = 0.009).

Conclusion: The coexistence of lesions evocative of NMOSD and in hAQP4 is associated with significantly more extensive myelitis, and might have pathophysiological and clinical significance.
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http://dx.doi.org/10.1016/j.neurad.2019.03.015DOI Listing
April 2019

Observatoire Français de la Sclérose en Plaques (OFSEP): A unique multimodal nationwide MS registry in France.

Mult Scler 2020 01 13;26(1):118-122. Epub 2018 Dec 13.

Department of Neurology, CHU de Toulouse, Toulouse, France.

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.
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http://dx.doi.org/10.1177/1352458518815602DOI Listing
January 2020

Weekly enhanced T1-weighted MRI with Gadobutrol injections in MS patients: Is there a signal intensity increase in the dentate nucleus and the globus pallidus?

Eur J Radiol 2018 Aug 19;105:204-208. Epub 2018 Jun 19.

Faculté de médecine Lyon Est, Université Claude Bernard Lyon 1, Université de Lyon, 69008, Lyon, France; CREATIS, CNRS UMR 5220 - INSERM U1206, Université de Lyon, 69621, Villeurbanne, France; Service de Radiologie, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, 69310, Pierre Bénite, France. Electronic address:

Background And Purpose: Gadolinium-based contrast agents (GBCAs) administration have drastically improved the accuracy of Multiple Sclerosis (MS) diagnosis by highlighting any damage to the brain blood barrier, thereby differentiating between active and non-active lesions. Following multiple administrations of GBCAs, several MS studies have reported a signal intensity (SI) increase on unenhanced T1-weighted images in certain brain regions such as the dentate nucleus (DN) and the globus pallidus (GP). Our aim was therefore to determine the accumulation of macrocyclic GBCAs on enhanced T1-weighted images SI in the DN and the GP of MS patients injected eight times.

Materials And Methods: Five MS patients underwent eight weekly consecutive MRI scans. Enhanced 3D T1-weighted images with Gadobutrol as a macrocyclic GBCA, were acquired. A ROI-based approach was applied for the evaluation of SI in the DN to middle cerebellar peduncle (DN-MCP) and GP to semi-oval white matter (GP-SOWM) ratios. An analysis of variance on repeated measures was used for the statistical analysis of each ratio.

Results: No DN-MCP and GP-SOWM SI ratio differences were observed over the eight-weeks period using the macrocyclic GBCA.

Conclusion: Iterative and weekly injections of macrocyclic GBCAs are not associated with T1 signal increase in the DN and GP of MS patients. These results would suggest a no gadolinium accumulation in the brain using macrocyclic GBCA even after several close injections and promote the use of a macrocylcic GBCA rather than linear agents for MS patients.
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http://dx.doi.org/10.1016/j.ejrad.2018.06.011DOI Listing
August 2018

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study.

Neurology 2018 05 25;90(21):e1858-e1869. Epub 2018 Apr 25.

Objective: To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis.

Methods: Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included.

Results: Median age at onset was 36.46 (range 18.0-76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26-0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22-0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07-0.72). Finally, MOG-Ab titers were higher at relapse than in remission ( = 0.009).

Conclusion: In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.
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http://dx.doi.org/10.1212/WNL.0000000000005560DOI Listing
May 2018

GCKR polymorphism influences liver fat content in patients with type 2 diabetes.

Acta Diabetol 2016 Apr 16;53(2):237-42. Epub 2015 May 16.

Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France.

Aims: It has recently been shown that an allele in the glucokinase regulatory protein (GCKR) gene was associated with increased liver fat content in obese children. In this study, we set out to determine whether GCKR rs1260326 polymorphism was associated with liver fat content in patients with type 2 diabetes.

Methods: Three hundred and eight patients with type 2 diabetes were included in this study. Liver fat content was evaluated using 1H-MR spectroscopy.

Results: In our population, carriers of the rs1260326 minor T allele had a higher liver fat content than did carriers of the C allele homozygote (12.4 ± 9.6 vs. 10.3 ± 9.1 %, p = 0.03). The number of patients with steatosis was significantly higher in minor T allele carriers than in C allele homozygote carriers (70.7 vs. 55.4 %; p = 0.008). In multivariate analysis, the predictive variables for steatosis were BMI [odds ratio (OR) 1.08; 95 % confidence interval (CI) 1.03-1.13; p = 0.002], statin therapy (yes) [OR 0.54; 95 % CI 0.31-0.94; p = 0.03], metformin therapy (yes) [OR 2.67; 95 % CI 1.50-4.75; p < 0.001], and rs1260326 GCKR polymorphism (TT+CT) [OR 1.99; 95 % CI 1.14-3.47; p = 0.01].

Conclusions: This study shows that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fat content was related to GCKR rs1260326 polymorphism independent of BMI, triglyceride levels, and age.
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http://dx.doi.org/10.1007/s00592-015-0766-4DOI Listing
April 2016

Incidence and patterns of late recurrences in colon cancer patients.

Int J Cancer 2015 Nov 6;137(9):2133-8. Epub 2015 May 6.

Digestive Cancer Registry of Burgundy F-21079, INSERM U866, CHU Dijon, University of Burgundy, France.

Long-term recurrences of colon cancer raised questions about the possible benefit of prolonging the recommended active 5-year surveillance. The aim of this study was to determine, for the first time, the incidence and patterns of late 10-year recurrence following curative resection of colon cancer. Data were obtained from two French digestive cancer registries. A total of 3,622 patients under 85 years resected for cure for colon cancer diagnosed between 1985 and 2000 were included. Information regarding recurrences was actively collected. Cumulative failure rates at 10 years were estimated using Kaplan-Meier estimates corrected by cause-specific hazards, and multivariable analysis was performed using a model for the subdistribution of a competing risk proposed by Fine and Gray. The overall cumulative recurrence rate between 5 and 10 years after initial surgery was 2.9% for local recurrence and 4.3% for distant metastasis. Among men with no recurrence 5 years after diagnosis of colon cancer, 1 in 12 developed a recurrence between 5 and 10 years, and the corresponding cumulative rate was 7.8%. The frequency was 1 in 19 for women, corresponding to a cumulative rate of 5.2%. In the multivariate analysis, non-emergency diagnostic feature, female sex and age under 75 were associated with a lower risk of recurrence. Stage at diagnosis was not a predictor of late recurrence. Late recurrence after colon cancer resection with curative intent can occur. A regular clinical follow-up is necessary to detect early signs of possible recurrence.
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http://dx.doi.org/10.1002/ijc.29578DOI Listing
November 2015

Conditional net survival: Relevant prognostic information for colorectal cancer survivors. A French population-based study.

Dig Liver Dis 2015 Jul 27;47(7):597-601. Epub 2015 Mar 27.

Digestive Cancer Registry of Burgundy, INSERM U866, University Hospital Dijon, University of Burgundy, Dijon, France.

Background: Traditionally, survival estimates have been reported as survival from the time of diagnosis. A patient's probability of survival changes according to time elapsed since the diagnosis and this is known as conditional survival. The aim was to estimate 5-year net conditional survival in patients with colorectal cancer in a well-defined French population at yearly intervals up to 5 years.

Methods: Our study included 18,300 colorectal cancers diagnosed between 1976 and 2008 and registered in the population-based digestive cancer registry of Burgundy (France). We calculated conditional 5-year net survival, using the Pohar Perme estimator, for every additional year survived after diagnosis from 1 to 5 years.

Results: The initial 5-year net survival estimates varied between 89% for stage I and 9% for advanced stage cancer. The corresponding 5-year net survival for patients alive after 5 years was 95% and 75%. Stage II and III patients who survived 5 years had a similar probability of surviving 5 more years, respectively 87% and 84%. For survivors after the first year following diagnosis, five-year conditional net survival was similar regardless of age class and period of diagnosis.

Conclusions: For colorectal cancer survivors, conditional net survival provides relevant and complementary prognostic information for patients and clinicians.
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http://dx.doi.org/10.1016/j.dld.2015.03.013DOI Listing
July 2015

Causes of death in people with chronic HBV infection: A population-based cohort study.

J Hepatol 2015 Jun 24;62(6):1265-71. Epub 2015 Jan 24.

Viral Hepatitis Registry, INSERM U866, France; Burgundy University, France; Department of Hepatogastroenterology, Dijon University Hospital, BP 87900, 21079 Dijon, France.

Background & Aims: Mortality related to hepatitis B virus (HBV) is not well known in developed countries. The aim of this study was to investigate in a population-based cohort the excess risk of death in HBV patients compared with mortality in the general population and to identify risk factors related to all-cause mortality and HBV-related mortality.

Methods: A specialized population-based registry has recorded data from patients with chronic HBV infection in a population of one million inhabitants in France since 1994. Standardized mortality rates for all-cause death and HBV-related death were calculated. Cumulative mortality rates were calculated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox model.

Results: Between 1994 and 2009, 1117 people were diagnosed with chronic HBV infection. Of these 136 (12.2%) died. All-cause mortality was significantly higher in HBV-infected people (standardized mortality ratio (SMR) 1.7 [1.4-2.0]). There was substantial excess mortality due to hepatocellular carcinoma (SMR 15.9 [10-24.1]), non-Hodgkin lymphoma (SMR 8.6 [3.1-18.6]) and liver disease (SMR 10.2 [5.8-16.6]). The cumulative rates for all-cause mortality were 8.6% at 5 years, 12.6% at 10 years and 18.5% at 15 years. The corresponding values for HBV-related mortality were 3.5%, 4.2%, and 5.8%. The multivariate analysis for all-cause mortality and for HBV-related mortality showed that male sex, age over 45 at diagnosis, current alcoholism and nosocomial risk factors were predictors of increased mortality.

Conclusion: This study shows increased all-cause mortality in HBsAg-positive patients, with considerable excess mortality due to chronic liver disease, hepatocellular carcinoma and non-Hodgkin lymphoma.
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http://dx.doi.org/10.1016/j.jhep.2015.01.020DOI Listing
June 2015

Incidence and patterns of late recurrences in rectal cancer patients.

Ann Surg Oncol 2015 Feb 27;22(2):520-7. Epub 2014 Aug 27.

Digestive Cancer Registry of Burgundy, INSERM U866, University Hospital Dijon, University of Burgundy, Dijon Cedex, France.

Background: Long-term recurrences of rectal cancer raised questions about the possible benefit of prolonging the recommended active 5-year clinical and endoscopic surveillance. The aim of this study was to determine for the first time, incidence and patterns of late 10-year recurrence after curative resection of rectal cancer.

Methods: The study included 1,222 patients with rectal cancer resected for cure between 1985 and 2000 from those registered in two French population-based digestive cancer registries. Information about local recurrences and distant metastases at 10 years was retrospectively and actively collected up to January 1, 2011.

Results: Although the overall 5-year cumulated rate was 39.5 %, the 10-year cumulated rate was 44.1 % (25.6 % for local recurrence and 29.9 % for distant metastases). In multivariate analyses, TNM stage was associated with a higher risk of local recurrence (hazard ratio [HR] stage III vs. stage I = 3.98 [95 % confidence interval, 2.66-5.94]) and of distant metastasis (HR = 3.60 [2.65-4.91]). Preoperative radiotherapy decreased the risk of local recurrence (HR = 0.43 [0.28-0.66]), but not the risk of metastasis. Patients diagnosed between 1995 and 2000 were less prone to develop long-term metastasis than those diagnosed between 1985 and 1989 (HR = 0.66 [0.49-0.88]). Among patients without recurrence 5 years after diagnosis, one patient in 13 developed a recurrence between 5 and 10 years.

Conclusions: Late recurrences do exist. A personalised surveillance could be extended until 10 years according to the characteristics of primary tumour and the patient.
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http://dx.doi.org/10.1245/s10434-014-3990-1DOI Listing
February 2015

Longitudinal study of alexithymia and multiple sclerosis.

Brain Behav 2014 Jan 18;4(1):75-82. Epub 2013 Dec 18.

Service de Neurologie Clinique Bourguignonne de la Sclérose en Plaques, University Hospital Dijon, France.

Objective: The aim of this study was to investigate the course of alexithymia and its relation with anxiety and depression in patients with multiple sclerosis (MS), over a period of 5 years.

Methods: Sixty-two MS patients were examined at two timepoints, 5 years apart, and they answered questionnaires collecting socio-demographic, medical, and psychological data (depression, anxiety, alexithymia).

Results: Our data show that emotional disorders remain stable over time in patients with MS, particularly as regards alexithymia and anxiety. Conversely, the rate of depression decreased between the two evaluations, falling from 40% to 26%. The two dimensions of alexithymia (i.e., difficulty describing and difficulty identifying feelings) were correlated with anxiety and depression, whereas the third component of alexithymia (externally oriented thinking) was independent, and was the only component to change over time, with a significant fall observed at 5 years.

Conclusion: Alexithymia was associated with increased severity of anxiety and attack relapses.
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http://dx.doi.org/10.1002/brb3.194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937709PMC
January 2014

Toxicity of oxaliplatin plus fluorouracil/leucovorin adjuvant chemotherapy in elderly patients with stage III colon cancer: a population-based study.

Ann Surg Oncol 2014 Aug 18;21(8):2636-41. Epub 2014 Mar 18.

Digestive Cancer Registry of Burgundy, INSERM U866, University Hospital, University of Burgundy, Dijon, France.

Background: Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice.

Methods: Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan-Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model.

Results: There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68-2.41; p = 0.439).

Conclusions: Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients' age alone, but consideration should be given to the capacity of patients to tolerate adverse events.
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http://dx.doi.org/10.1245/s10434-013-3438-zDOI Listing
August 2014

Impact of liver disease severity and etiology on the occurrence of diabetes mellitus in patients with liver cirrhosis.

Acta Diabetol 2014 19;51(3):455-60. Epub 2013 Dec 19.

University Hospital Dijon, Dijon, France,

The association between liver cirrhosis (LC) and diabetes mellitus (DM) is well known. However, the impact of the severity or etiology of LC on the occurrence of DM is relatively unknown. We aimed to determine the prevalence and clinical correlates of DM in a large cohort of patients with cirrhosis. A total of 1,068 patients with LC were included in this cross sectional study (CIRCE study). The diagnosis of cirrhosis irrespective of its etiology was based on histological confirmation by liver biopsy or, in the absence of biopsy, on typical clinical, morphological and biological data. Data related to the cirrhosis etiology: alcohol, viral markers of hepatitis B, C, iron load parameters and autoimmune markers were collected for each patient. Venous blood samples were taken in the morning after 12-h overnight fasting. There were 383 patients with cirrhosis associated with hepatocellular carcinoma (HCC). DM was found in 412 (39.7 %) patients. Patients with DM were older and more likely to be overweight and male, with a family history of DM and a diagnosis of HCC. DM was not associated with a history of stroke or myocardial infarction. Cirrhosis secondary to hepatitis infection was less strongly associated with DM than with NASH or alcoholic cirrhosis. The severity of LC was not associated with DM. In multivariate analysis, the factors associated with DM were age, BMI, a family history of DM, and statin use. There was a significant interaction between HCC and cirrhosis etiology for the risk of DM. Cirrhosis secondary to hepatitis was associated with a lesser presence of DM only in patients with HCC (interaction p = 0.0015). LC was strongly associated with DM, with around 40 % of diabetic patients. In the group of patients with LC without HCC, diabetes was not associated with the etiology of cirrhosis.
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http://dx.doi.org/10.1007/s00592-013-0538-yDOI Listing
January 2015

Comorbidities at multiple sclerosis diagnosis.

J Neurol 2013 Oct 2;260(10):2629-37. Epub 2013 Aug 2.

Department of Neurology, University Hospital of Dijon, 3 rue du Faubourg Raines, 21000, Dijon, France.

The nature and frequency of comorbidities upon notification of multiple sclerosis (MS) are not well known. In France, MS is one of the 30 long-term illnesses (affections de longue durée, ALD) for which 100 % of patients' health care costs are covered by the main French health insurance system. We conducted a study among 22,087 patients who had contracted MS before their 45th birthday and had obtained ALD status between 1995 and 2004. Comorbidities diagnosed at MS notification were described. The age at which MS was registered in patients with a previous comorbidity was compared with that in those patients with no previous comorbidities. Among the 22,087 patients, 21,119 (95 %) had ALD status for MS only, 653 (3 %) had a comorbidity status diagnosed at the same time as MS. Of these comorbidities, 86.8 % could be grouped into five main categories: psychiatric disease (40.2 %), autoimmune disease (24.5 %), cardiovascular disease (16.2 %), cancer (12.2 %), and metabolic disease (9.0 %). Psychiatric disorders and diabetes were more frequent in MS patients than in the general population of the same age. The mean age at request for ALD status for MS in patients with no comorbidity was 33.6 ± 7.2 years, whereas it was 36.9 ± 6.5 years in those with comorbidities. Comorbidities at MS notification are rare. Psychiatric disorders and diabetes were more frequent in MS patients than in the general population.
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http://dx.doi.org/10.1007/s00415-013-7041-9DOI Listing
October 2013

Liver fat content is associated with an increase in cholesterol synthesis independent of statin therapy use in patients with type 2 diabetes.

Atherosclerosis 2012 Oct 20;224(2):465-8. Epub 2012 Aug 20.

Centre de Recherche INSERM Unité 866, CHU du Bocage, BP 77908, 21079 Dijon Cedex, France.

Unlabelled: We investigated how liver fat content (LFC) influences cholesterol metabolism by quantifying liver fat using proton magnetic resonance spectroscopy and by measuring the serum concentrations of lathosterol, a marker of cholesterol synthesis, and sitosterol and campesterol, two markers of cholesterol absorption. We also evaluated whether this relationship could be modified by statin therapy. The study was conducted in 263 patients with type 2 diabetes, 137 of whom (52.0%) received statin therapy.

Results: One hundred and sixty-five patients (62.7%) had steatosis (LFC>5.5%). We performed specific analyses in patients without statin therapy and in patients treated with statin therapy. In both groups, the lathosterol to cholesterol ratio correlated positively with LFC, and in multivariate analysis, the lathosterol to cholesterol ratio was associated with LFC independently of age, gender and BMI. Sitosterol and campesterol concentrations were not associated with LFC.

Conclusions: Our study suggests that in patients with type 2 diabetes, LFC is associated with an increase in cholesterol synthesis that is independent of obesity or diabetes mellitus. Statin therapy does not modify this relationship.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.08.016DOI Listing
October 2012